Although RNA targets in the transcriptome are numerous, there is a dearth of small molecule chemical probes that can be used to study RNA function and dysfunction. Despite great interest in this area, the development of such compounds is difficult owing to a lack of fundamental information, or design principles, that could enable the design of compounds that selectively target RNA in a cell.
One approach to design compounds that affect function is to study RNA motif-small molecule interactions, thereby identifying small molecule “modules” that bind regions of an RNA of interest. Affinity and selectivity of the modules can be improved by linking them together to bind two or more regions in the desired RNA. Indeed, such a bottom-up approach has been used to design compounds that target repeating transcripts and other RNAs.
Covalent adduct formation between small molecules and DNA has been an effective therapeutic strategy for cancer.1 However, analogous approaches for disease-associated RNAs have been only sparsely reported.2 
RNA is an interesting and increasingly important drug target due to its essential functions and association with various diseases. Yet, there are relatively few small molecules that target RNAs in living cells and affect function.3 The bacterial ribosome is the most well studied target of small molecules, which have served as therapeutics and probes of ribosomal function.4 Compounds targeting other RNAs are needed to enable similar studies, yet few have been reported.
The development of small molecule chemical probes or therapeutics that target RNA remains a significant challenge despite the great interest in such compounds. The most significant barrier to compound development is a lack of knowledge of the chemical and RNA motif spaces that interact specifically.
Myotonic dystrophy (dystrophia myotonica, myotonia atrophica) is a chronic, slowly progressing, highly variable, inherited multisystemic disease. It is characterized by wasting of the muscles (muscular dystrophy), cataracts, heart conduction defects, endocrine changes, and myotonia. Two types of myotonic dystrophy exist. Type 1 (DM1), also known as Steinert disease, has a severe congenital form and a milder childhood-onset form as well as an adult-onset form.
RNA plays diverse and important roles in biological processes, including myotonic dystrophy type 1 (DM1).5 DM1 is caused when expanded repeats present in UTR's sequester proteins that are involved in pre-mRNA splicing regulation. Sequestration of these proteins causes the aberrant splicing of a variety of pre-mRNAs, leading to the expression of defective proteins. Thus, DM1 is caused by an RNA gain-of-function.
In addition to RNA gain-of-function, repeating transcripts can also cause disease via by their translation into toxic proteins with or without the use of a start codon.6e A common defect caused by the gain-of-function by expanded repeats is dysregulation of alternative pre-mRNA splicing.7c For example, fragile X-associated tremor/ataxia syndrome (FXTAS) is caused by an expanded r(CGG) repeat (r(CGG)exp), which binds and sequesters various proteins including DiGeorge Syndrome Critical Region 8 protein (DGCR8), Src-associated in mitosis, 68 kDa protein (Sam68), and others.8b,9b Sequestration of these proteins causes deregulation of the microRNA processing and alternative pre-mRNA splicing.8b,9b As has been demonstrated for the RNAs that cause the myotonic dystrophies, amyotrophic lateral sclerosis, and FXTAS, expanded repeating RNAs are also translated without the use of a start codon, or repeat-associated non-ATG (RAN) translation.10b,11b,12b RAN translation produces toxic polymeric proteins that appear to contribute to disease.